leukotriene-d4 and Leukemia--Myeloid--Acute
leukotriene-d4 has been researched along with Leukemia--Myeloid--Acute* in 2 studies
Other Studies
2 other study(ies) available for leukotriene-d4 and Leukemia--Myeloid--Acute
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Induction of granulocytic differentiation in myeloblasts by hydroquinone, a metabolite of benzene, involves the leukotriene D4 receptor.
Chronic exposure of humans to benzene (BZ), a Class I carcinogen, causes acute myelogenous leukemia, possibly via its bone marrow metabolite, hydroquinone (HQ). The ability to alter cytokine-dependent growth and differentiation in hematopoietic stem or progenitor cells appears to be a property of agents with leukemogenic potential. We have previously reported that BZ and HQ specifically stimulate granulopoiesis in mice and cause granulocytic differentiation in normal murine interleukin (IL)-3-dependent, granulocyte colony-stimulating factor (G-CSF)-inducible 32D myeloblasts. BZ induces granulocytic differentiation by upregulating the production of leukotriene D4 (LTD4), an essential intracellular mediator of G-CSF signaling. We report here that HQ (0.5-4.0 microM), as well as LTD4 (1 nM-10 microM), causes a concentration-dependent induction of granulocytic differentiation in 32D myeloblasts. Unlike LTD4, which induces terminal granulocytic differentiation, HQ undergoes a myeloperoxidase-dependent oxidation to bioreactive p-benzoquinone (BQ), which induces differentiation predominantly to the myelocyte stage. Studies with the highly specific LTD4 receptor antagonist, MK-571, suggest that BQ induces granulocytic differentiation in myeloblasts by activating the LTD4 receptor, thus obviating the requirement for LTD4. This was confirmed by the demonstration that HQ, in the presence of LTD4, shifts the stage-specific pattern of terminal differentiation induced by LTD4 to the incomplete (myelocyte) profile induced by HQ. The inability of HQ to induce a complete program of terminal granulocytic differentiation in myeloblasts, as well as its ability to compete with induction by LTD4, may have a bearing on the leukemogenic potential of BZ. Topics: Animals; Benzene; Cell Differentiation; Cell Line; Granulocyte Colony-Stimulating Factor; Granulocytes; Hematopoiesis; Hematopoietic Stem Cells; Humans; Hydroquinones; Indomethacin; Leukemia, Myeloid, Acute; Leukotriene Antagonists; Leukotriene D4; Membrane Proteins; Mice; Peroxidase; Propionates; Quinolines; Receptors, Leukotriene; Signal Transduction | 1996 |
Induction of granulocytic differentiation in a mouse model by benzene and hydroquinone.
Chronic exposure of humans to benzene causes acute myelogenous leukemia (AML). The studies presented here were undertaken to determine whether benzene, or its reactive metabolite, hydroquinone (HQ), affects differentiation of myeloblasts. Benzene or HQ administered to C57BL/6J mice specifically induced granulocytic differentiation of myeloblasts. The ability of these compounds to induce differentiation of the myeloblasts was tested directly using the murine interleukin 3 (IL-3)-dependent 32D.3 (G) myeloblastic cell line, and the human HL-60 promyelocytic leukemia cell line. We have previously shown that benzene treatment of HL-60 myeloblasts activates protein kinase C (PKC) and upregulates the 5-lipoxygenase (LPO) pathway for the production of leukotriene D4 (LTD4), an essential effector or granulocytic differentiation. Differentiation was prevented by sphinganine, a PKC inhibitor, and, as shown here, by LPO inhibitors and LTD4 receptor antagonists. Benzene or HQ also induces differentiation in 32D.3 (G) myeloblasts. Both compounds interact with cellular signaling pathways normally activated by granulocyte colony stimulating factor (G-CSF) and can replace the requirement for G-CSF. While IL-3 induces a growth response in 32D.3 (G) cells, G-CSF has been shown to provide both growth and differentiated signals. Both HQ and LTD4 induce differentiation and synergize with IL-3 for growth; however, neither supports growth in the absence of IL-3. Benzene, like HQ, also provides a differentiation signal for 32D cells; however, it has no effect on their growth. Unlike G-CSF, benzene, or LTD4, each of which stimulates terminal differentiation; HQ blocks differentiation at the myelocyte stage, allowing only a small percentage of progenitors to proceed to mature segmented granulocytes. Benzene- and G-CSF-induced differentiation were prevented by the additional of either LPO inhibitors or LTD4 receptor antagonists, indicating that benzene, like G-CSF, upregulates LTD4 production. Hydroquinone-induced differentiation was not affected by the LPO inhibitors, but only by the specific receptor antagonists. Thus HQ appears to obviate the requirement for LTD4 by activating the LTD4 receptor directly. Topics: Animals; Arachidonate 5-Lipoxygenase; Benzene; Carcinogens; Cell Differentiation; Granulocytes; HL-60 Cells; Humans; Hydroquinones; Leukemia, Myeloid, Acute; Leukotriene Antagonists; Leukotriene D4; Lipoxygenase Inhibitors; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Protein Kinase C; Receptors, Leukotriene | 1996 |